Four-chamber pacing system for optimizing cardiac output and determing heart condition

ABSTRACT

A pacing system and method for providing multiple chamber pacing of a patient&#39;s heart, and in particular, pacing programmed for treatment of various forms of heart failure. The system utilizes impedance sensing for determining optimum pacing parameters, e.g., for pacing the left ventricle so that left heart output is maximized. The impedance sensing also is used for determination of arrhythmias or progression of heart failure. Impedance sensing is provided for between selected pairs of the four chambers, to enable optimizing of information for control and diagnosis. In a preferred embodiment of the invention impedance measurements are obtained for determining the timing of right heart valve closure or right ventricular contractions, and the timing of delivery of left ventricular pace pulses is adjusted so as to optimally synchronize left ventricular pacing with the right ventricular contractions. Impedance sensing in the left heart also provides timing of mechanical contraction, and the pacemaker controls pacing to maintain bi-ventricular mechanical synchronization adjusted for maximum cardiac output.

FIELD OF THE INVENTION

[0001] This invention relates to cardiac pacing systems and, moreparticularly, to four-chamber pacing systems with sensors for measuringcardiac mechanical characteristics so as to improve cardiac output forcongestive heart failure and other patients.

BACKGROUND OF THE INVENTION

[0002] Congestive heart failure (CHF) is defined generally as theinability of the heart to deliver enough blood to the peripheral tissuesto meet metabolic demands. Frequently CHF is manifested by left heartdysfunction, but it can have a variety of sources. For example, CHFpatients may have any one of several different conduction defects. Thenatural electrical activation system through the heart involvessequential events starting with the sino-atrial (SA) node, andcontinuing through the atrial conduction pathways of Bachmann's bundleand internodal tracts at the atrial level, followed by theatrio-ventricular (AV) node, Common Bundle of His, right and left bundlebranches, and final distribution to the distal myocardial terminals viathe Purkinje fiber network. A common type of intra-atrial conductiondefect is known as intra-atrial block (IAB), a condition where theatrial activation is delayed in getting from the right atrium to theleft atrium. In left bundle branch block (LBBB) and right bundle branchblock (RBBB), the activation signals are not conducted in a normalfashion along the right or left bundle branches respectively. Thus, in apatient with bundle branch block, the activation of the ventricle isslowed, and the QRS is seen to widen due to the increased time for theactivation to traverse the conduction path.

[0003] CHF manifested by such conduction defects and/or othercardiomyopathies are the object of considerable research into treatmentsfor improving cardiac output. For example, drug companies haverecognized CHF as a market opportunity, and are conducting extensiveclinical studies organized to test the outcome of newly developed drugsin terms of improving cardiac performance in these patients. Likewise,it is known generally that four-chamber cardiac pacing is feasible, andcan provide significant improvement for patients having leftatrial-ventricular dysfunction, or other forms of cardiac heart failure.While there has been relatively little commercialization of four-chamberpacing, the hypothesis remains that cardiac pump function can clearly beimproved by such pacing.

[0004] The benefits of four-chamber pacing generally have been disclosedand published in the literature. Cazeau et al., PACE, Vol. 17, November1994, Part II, pp. 1974-1979, disclose investigations leading to theconclusion that four-chamber pacing is feasible, and that in patientswith evidence of interventricular dyssynchrony, a better mechanicalactivation process can be obtained by resynchronizing depolarization ofthe right and left ventricles, and optimizing the AV sequence on bothsides of the heart. In the patent literature, U.S. Pat. No. 4,928,688 isrepresentative of a system for simultaneous left ventricular (LV) andright ventricular (RV) pacing; natural ventricular depolarizations aresensed in both chambers, if one chamber contracts but the other one doesnot within a window of up to 5-10 ms, then the non-contractingventricular chamber is paced.

[0005] In addition to the above-mentioned disclosures concerning theadvantages of substantially simultaneous or synchronous pacing of thetwo ventricles, it is known that there is an advantage to synchronouspacing of the left atrium and the right atrium for patients with IAB,inter-atrial block. In a normal heart, atrial activation initiates withthe SA node, located in the right atrial wall. In a patient with IAB,the activation is slow being transferred over to the left atrium, and asa result the left atrium may be triggered to contract up to 90 ms laterthan the right atrium. It can be seen that if contractions in the leftventricle and the right ventricle are about the same time, then left AVsynchrony is way off, with the left ventricle not having adequate timeto fill up. The advantage of synchronous pacing of the two atria forpatients with IAB is disclosed at AHA 1991, Abstract from 64thScientific Sessions, “Simultaneous Dual Atrium Pacing in High DegreeInter-Atrial Blocks: Hemodynamic Results,” Daubert et al., No. 1804.Further, it is known that patients with IAB are susceptible toretrograde activation of the left atrium, with resulting atrialtachycardia. Atrial resynchronization through pacing of the atria can beeffective in treating the situation. PACE, Vol. 14, April 1991, Part II,p. 648, “Prevention of Atrial Tachyarrythmias Related to Inter-AtrialBlock By Permanent Atrial Resynchronization,” Mabo et al., No. 122. Forpatients with this condition, a criterion for pacing is to deliver aleft atrial stimulus before the natural depolarization arrives in theleft atrium.

[0006] In view of the published literature, it is observed that in CHFpatients improved pump function can be achieved by increasing thefilling time of the left ventricle, i.e., improving the left AV delay,and specifically the left heart mechanical AV delay (MAVD); decreasingmitral valve regurgitation, (back flow of blood through the nearlyclosed valve) by triggering contraction of the left ventricle when andas it becomes filled; and normalizing the left ventricular activationpattern, i.e., the time sequence of left atrial contraction relative toright atrial contraction. More specifically, for a cardiac pacing systemused for treating a CHF patient, the aim is to capture the left atrium;optimize the left AV delay so as to properly fill the left ventricle andprovide a more normal AV delay; and activate the left ventricle as muchas possible in accordance with the natural propagation path of a healthyleft heart. Particularly, left ventricular timing with respect to theleft atrial contraction is crucial for improving cardiac output. Themechanical closure point of the left, or mitral valve, is a crucialmoment which needs to be adjusted by programming of the left AV delay.Correct programming of this variable is key for optimizing the fillingof the left ventricle, and optimizing ejection fraction, or cardiacoutput (CO).

[0007] An observation which is important to this invention is that theexact timing of mechanical events are important for properly controllingpacing so as to optimize left ventricular output. Specifically, it isknown that actual contraction of one ventricular chamber before theother has the effect of moving the septum so as to impair fullcontraction in the later activated chamber. Thus, while concurrent orsimultaneous pacing of the left and right ventricle may achieve asignificant improvement for CHF patients, it is an aim of this inventionto provide for pacing of the two ventricles in such a manner that theactual mechanical contraction of the left ventricle, with the consequentclosing of the valve, occurs in a desired time relationship with respectto the mechanical contraction of the right ventricle and closing of theright value. For example, if conduction paths in the left ventricle areimpaired, delivering a pacing stimulus to the left ventricle atprecisely the same time as to the right ventricle may nonetheless resultin left ventricular contraction being slightly delayed with respect tothe right ventricular contraction. As a consequence, it is important forthis invention to provide a technique for measurement of mechanicalevents, such as a mechanical closure point of each of the ventricles, soas to be able to accurately program the sequence of pacing to achievethe desired dual ventricular pacing which optimizes ejection fraction,or cardiac output, for the individual patient.

[0008] In view of the above-noted importance of measuring mechanicalevents, such as mitral or tricuspid valve closure, and the importance ofmeasuring cardiac output, it is necessary for the pacing system of thisinvention to employ sensors which can provide this information. It isknown to use impedance sensors in pacing systems, for obtaininginformation concerning cardiac function. For example, reference is madeto U.S. Pat. No. 5,501,702, incorporated herein by reference, whichdiscloses making impedance measurements from different electrodecombinations. In such system, a plurality of pace/sense electrodes aredisposed at respective locations, and different impedance measurementsare made on a time/multiplexing basis. As set forth in the referencedpatent, the measurement of the impedance present between two or moresensing locations is referred to “rheography.” A rheographic, orimpedance measurement involves delivering a constant current pulsebetween two “source” electrodes, such that the current is conductedthrough some region of the patient's tissue, and then measuring thevoltage differential between two “recording” electrodes to determine theimpedance therebetween, the voltage differential arising from theconduction of the current pulse through the tissue or fluid between thetwo recording electrodes. The referenced patent discloses usingrheography for measuring changes in the patient's thoracic cavity;respiration rate; pre-ejection interval; stroke volume; and heart tissuecontractility. It is also known to use this technique of four pointimpedance measurements, applied thoracically, for measuring smallimpedance changes during the cardiac cycle, and extracting the firsttime derivative of the impedance change, dZ/dt. It has been found that asubstantially linear relation exists between peak dZ/dt and peak cardiacejection rate, providing the basis for obtaining a measure of cardiacoutput. See also U.S. Pat. No. 4,303,075, disclosing a system formeasuring impedance between a pair of electrodes connected to or inproximity with the heart, and processing the variations of sensedimpedance to develop a measure of stroke volume. The AV delay is thenadjusted in an effort to maximize the stroke volume.

[0009] Given the demonstrated feasibility of four-chamber cardiacpacing, and the availability of techniques for sensing natural cardiacsignals and mechanical events, there nonetheless remains a need fordeveloping a system which is adapted to the cardiac condition of apatient with CHF, so as to provide pacing sequences which are tuned forimproving cardiac output, and in particular for improving left heartfunction. It is a premise of this invention that such a system isfounded upon accurate measurements of mechanical events, and use of thetiming of such mechanical events to control and program pacingsequences.

SUMMARY OF THE INVENTION

[0010] It is an overall object of this invention to provide a pacingsystem for multiple chamber pacing, and in particular, for pacing thepatient's left heart in coordination with the electrical activation andmechanical events of the patient's right heart, so as to optimize leftheart output. In accordance with this invention, there is provided afour-chamber pacing system, having leads carrying electrodes positionedfor pacing and sensing in or on each of the four cardiac chambers.Additionally, the leads are connected to obtain impedance measurementsfrom which accurate timing signals are obtained reflecting mechanicalactions, e.g., valve closures, so that accurate timing information isavailable for controlling electrical activation and resultant mechanicalresponses for the respective different chambers. The impedance ormechanical sensing determinations are preferably made by multi-plexingthrough fast switching networks to obtain the desired impedancemeasurements in different chambers.

[0011] In a preferred embodiment, control of four-chamber pacing, and inparticular left heart pacing, is based primarily upon initial detectionof a spontaneous signal in the right atrium, and upon sensing ofmechanical contraction of the right and left ventricles. In a heart withnormal right heart function, the right mechanical AV delay is monitoredto provide the timing between the initial sensing of right atrialactivation (P-wave) and right ventricular mechanical contraction. Theleft heart is controlled to provide pacing which results in leftventricular mechanical contraction in a desired time relation to theright mechanical contraction; e.g., either simultaneous or justpreceding the right mechanical contraction; cardiac output is monitoredthrough impedance measurements, and left ventricular pacing is timed tomaximize cardiac output. In patients with intra-atrial block, the leftatrium is paced in advance of spontaneous depolarization, and the leftAV delay is adjusted so that the mechanical contractions of the leftventricle are timed for optimized cardiac output from the leftventricle.

BRIEF DESCRIPTION OF THE DRAWINGS

[0012]FIG. 1 is a schematic representation of a system in accordancewith this invention, whereby four bipolar leads are provided, the leadsbeing shown carrying bipolar electrodes positioned in each of therespective cardiac chambers.

[0013]FIG. 2A is a block diagram of a four channel pacing system inaccordance with this invention, for pacing and sensing in eachventricle, and for obtaining impedance signals from the left heart andthe right heart; FIG. 2B is a schematic representation of an arrangementin accordance with this invention for detecting left ventricularimpedance for determination of cardiac output.

[0014]FIG. 3 is a block diagram of a four-chamber pacemaker with theability to time multiplex impedance measurements, in accordance withthis invention.

[0015]FIG. 4 is a block diagram of a system implementation in accordancewith an embodiment of this invention for controlling left ventricularpacing in a patient with LBBB.

[0016]FIG. 5 is a flow diagram for a system implementation in accordancewith an embodiment of this invention, for controlling left atrial andventricular pacing in a patient with IAB.

[0017]FIG. 6 is a flow diagram of a routine in accordance with thisinvention for optimizing bi-ventricular pacing to provide maximumcardiac output.

[0018]FIG. 7 is a block schematic of a pacemaker in accordance with thisinvention for providing selectable four-chamber pacing and cardiacsignal sensing, as well as impedance sensing between selectedcombinations of the four heart chambers.

[0019]FIG. 8A is a flow diagram of a process using inter-atrial orinter-ventricular impedance measurements for determination of existenceof arrhythmias; FIG. 8B is a flow diagram illustrating a procedure forobtaining atrio-ventricular cross-impedance measurements for obtainingindications of heart failure.

DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0020] In the description of the preferred embodiments, and withreference to the drawings, the following designations are used: DRAWINGDESIGNATION DEFINITION RA right atrium RV right ventricle RH RA and RVLH LA and LV LA left atrium LV left ventricle LAS left atrial sense RASright atrial sense LAP left atrial pace pulse LVP left ventricular pacepulse RMAVD time interval between RAS and mechanical contraction of RV(as measured, e.g., by valve closure) LMAVD time interval between LAS orLAP and mechanical contraction of LV RAVD time interval between RAS andQRS in RV LAVD time interval between LAS or LAP, and QRS in LV

[0021] Referring now to FIG. 1, there is shown a schematicrepresentation of a four-chamber pacing system, illustrating four pacingleads providing bipolar electrodes positioned for pacing and sensing ineach of the respective heart chambers, and also for impedancemeasurements. Pacing lead 38 is positioned conventionally such that itsdistal end is in the right ventricular apex position. It carries bipolarelectrodes 38 a and 38 b adapted for pacing and sensing; additionally,these electrodes can also be used for impedance sensing as discussedbelow. Likewise, atrial lead 36 is positioned so that its distal end ispositioned within the right atrium, with bipolar electrodes 36 a, 36 b.Lead 34 is passed through the right atrium, so that its distal end ispositioned in the coronary sinus for pacing, sensing and impedancedetection through electrodes 34 a, b, as shown. Likewise, lead 32 ispositioned via the coronary sinus a cardiac vein, e.g., the middle orgreat cardiac vein, so that distal electrodes 32 a and 32 b arepositioned approximately as shown for pacing, sensing and impedancedetection with respect to the left ventricle. The pacing leads areconnected to pacemaker 30 in a conventional manner. It is to beunderstood that each of the four leads can have one or more additionalelectrodes; however, by using time multiplexing techniques as discussedbelow and in the referenced U.S. Pat. No. 5,501,702, pacing, sensing andimpedance detection can be accomplished with only two electrodes perlead. Referring now to FIGS. 2A and 2B, there is shown a simplifiedblock diagram of a four channel pacemaker in accordance with thisinvention, having the additional capability of impedance detection tosense valve movement of the left and right ventricles. Althoughdiscussion of FIG. 2A is presented with respect to valve movement, it isto be understood that the impedance detection scheme may be altered todetect other mechanical events, such as ventricular wall contraction, ina known manner.

[0022] The system of FIG. 2A contains, in the pacemaker, a centralprocessing block 40, indicated as including timing circuitry and amicroprocessor, for carrying out logical steps in analyzing receivedsignals, determining when pace pulses should be initiated, etc., in awell known fashion. Referring to the upper left-hand corner of the blockdiagram, there is shown signal amplifier circuitry 41, for receiving asignal from the right atrium. Electrode 36 a is illustrated as providingan input, it being understood that the second input is received eitherfrom bipolar electrode 36 b, or via an indifferent electrode (thepacemaker can) in the event of unipolar sensing. Likewise, a pulsegenerator 42, acting under control of block 40, generates right atrialpace pulses for delivery to electrode 36 a and either electrode 36 b orsystem ground. In a similar manner, right ventricular pace pulses (RVP)are generated at output stage 43 and connected to electrode 38 a, andsensed right ventricular signals are inputted to sense circuitry 44, theoutput of which is delivered to control block 40. Also illustrated isimpedance detector 45, which receives inputs from electrodes 36 a, 38 a,for delivering information corresponding to right heart valve closure,which timing information is inputted into control block 40. Thus, thesystem enables pacing and sensing in each chamber, as well as impedancedetection to provide an indication of the timing of right heart valveclosure, which represents the time of mechanical contraction of theright valve.

[0023] Still referring to FIG. 2A, there are shown complementary circuitcomponents for the left atrium and the left ventricle. Output generatorstage 47, under control of block 40, delivers left atrial pace pulses(LAP) to stimulate the left atrium through electrode 34 a and eitherelectrode 34b or system ground. Inputs from the left atrial lead areconnected through input circuitry 46, the output of which is connectedthrough to control block 40. In a similar fashion, output stage 48,under control of block 40, provides left ventricular stimulus pacepulses (LVP) which are delivered across electrode 32 a and eitherelectrode 32 b or system ground; and left ventricular signals are sensedfrom lead 32 and inputted to input circuit 49, which provides an outputto block 40 indicative of left ventricular signals. Also, dual inputsfrom the left atrial electrode 34 a and left ventricular electrode 32 aare inputted into left heart impedance detector 50, which providestiming pulses to block 40 indicative of the timing of left heart(mitral) valve closure. With this arrangement, the pacemaker has thebasic timing and cardiac signal information required to program deliveryof pace pulses to respective heart chambers in accordance with thisinvention. Block 40 contains current generators for use in impedancedetection; microprocessor or other logic and timing circuitry; andsuitable memory for storing data and control routines.

[0024] Referring to FIG. 2B, there is shown a diagrammatic sketch of anarrangement for detecting left ventricular impedance change, which isprocessed in block 40 to obtain an indication of cardiac output. Asshown, a current source 52 provides a constant current source acrosselectrode 53 in the right atrium, which suitably can be electrode 36 a;and right ventricular electrode 54, which suitably can be electrode 38a. The current source can be pulsed, or it can be multiplexed in amanner as discussed below. Impedance sensors 57 and 58 provide signalsrepresentative of impedance changes therebetween, the impedance being afunction of blood volume and valve closure, as discussed above. Theoutputs from electrodes 57, 58 is connected across impedance detector56, which represents the microprocessor and/or other processingcircuitry in block 40 for analyzing the impedance changes and making adetermination of cardiac output. As is known, a measure of cardiacoutput can be obtained by extracting the first time derivative ofcyclical impedance changes, dz/dt; a linear relationship exists betweenpeak dz/dt and peak ejection rate.

[0025] Referring now to FIG. 3, there is shown a block diagram of apacemaker 30 in accordance with a preferred embodiment of thisinvention, for multiplexing connections to electrodes so as to providefor pacing and sensing in any one of the four cardiac chambers, as wellas for impedance determinations between respective different leadelectrodes. Reference is made U.S. Pat. No. 5,501,702, incorporatedherein by reference, for a full discussion of this circuit, and inparticular the multiplexing arrangement carried out by switch matrices68, 70. The pacemaker 30 operates under control of circuitry 62, whichmay include a microprocessor or custom integrated circuitry, as well asassociated memory, in a manner well known in the pacemaker art.Circuitry 62 provides for processing of data, and generation of timingsignals as required. Control circuitry 62 is coupled to pace/sensecircuitry 64, for processing of signals indicating the detection ofelectrical cardiac events, e.g., P-waves, R-waves, etc. sensed fromconductors which connect electrically to electrodes 32 a-38 b, as shown.The aforementioned leads are also coupled to a first switch matrix 68and a second switch matrix 70. Matrix 68 establishes a selectableinterconnection between specific ones of the electrodes of leads 32, 34,36 and 38, and the current source 72, is controlled by circuit 62. In asimilar manner, switch matrix 70 establishes a selectableinterconnection between lead conductors corresponding to selectedelectrodes, and impedance detection circuit 74, for the purpose ofselecting impedance measurements.

[0026] Still referring to FIG. 3, current source 72 receives controlsignals on line 73 from circuitry 62, and is responsive thereto fordelivering constant current rheography pulses onto lead conductorsselected by switching matrix 68, which in turn is switched by signals onbus 83. Impedance detection circuit 74 is adapted to monitor the voltagebetween a selected pair of electrodes which pair is selectably coupledby operation of switch matrix 70 which in turn is switched by signals onbus 80. In this manner, circuit 74 determines the voltage, and hence theimpedance, existing between two selected electrodes. The output ofcircuitry 74 is connected through A/D converter 76 to control circuitry62, for processing of the impedance signals and determination of theoccurrence of mechanical events, such as left or right heart valveclosure. The control of switch matrix 68 through signals on bus 78, andthe control of switch matrix 70 through signals on bus 80, provides formultiplexing of different impedance signals.

[0027] It is to be understood that in the system arrangement of FIG. 3,pace/sense circuitry 64 may include separate stimulus pulse outputstages for each channel, i.e., each of the four-chambers, each of whichoutput stages is particularly adapted for generating signals of theprogrammed signal strength. Likewise, the sense circuitry of block 64may contain a separate sense amplifier and processor circuitry forsensed signals from each chamber, such that sensing of respective waveportions, such as the P-wave, R-wave, T-wave, etc. from the RH and theLH, can be optimized. The pulse generator circuits and sense circuits asused herein are well known in the pacemaker art. In addition, otherfunctions may be carried out by the control circuitry including standardpacemaker functions such as compiling of diagnostic data, modeswitching, etc.

[0028] Referring now to FIG. 4, there is shown a logic control flowdiagram for controlling the system of this invention to pace a patientwith LBBB. The assumption is that the RH is normal, and that sinussignals from the SA node are being normally conducted to the LA; butthat the LBBB is manifested by slow conduction to the LV, such that theLV does not contract when it should. As a consequence, there is mitralregurgitation, or backflow of blood through the valve because the LVdoes not contract when it is filled from the LA; and the contraction ofthe LV, when it occurs, is later than that of the RV, furthercontributing to decrease of LH output.

[0029] As seen at 101, the pacemaker monitors the RH, and gets a measureof RMAV. This is done by sensing right valve closure through RHimpedance measurement, and timing the delay from the atrialdepolarization (RAS) to valve closure. Then, at 102, the pacemaker iscontrolled to pace LV with an LAVD such that LMAVD is about equal toRMAVD. During this step, impedance measurements are made in the LV, anda measure of LMAVD is obtained. Based on this determination, the valueof LAVD is adjusted to substantially match LMAVD with RMAVD. Note thatnormal conduction through the LV takes on the order of 50-60 ms, so itis expected that the LV should be paced in advance of the occurrence ofRV valve closure, so that LV valve closure occurs at about the same timeas, or even a bit before RV valve closure. Causing the LV to contractjust before the RV might provide an increase of LH output whichoutweighs the small resulting RV dysfunction due to the septum beingpulled toward the LV first. Thus, the timing of delivery of each LVP isadjusted to set LMAVD approximately equal to RMAVD. Then, at 104, thevalue of LAVD is further adjusted, while R and L valve closure ismonitored, and LMAVD is adjusted relative to RMAVD. This adjustment, orvariation of LMAVD, may be made by incrementally changing LAVD eachcycle, or each n cycles, to scan relative to the value of RMAVD. Cardiacoutput is obtained through a left heart impedance measurement, andappropriate signal processing, for each setting of the differentialbetween the right and left valve closures, and respective values of COand LMAVD are stored at 105. The highest, or maximum value of cardiacoutput is determined, and LAVD is set so that the resultant MLAVD is atthe differential compared to RMAVD to yield the highest cardiac output.In this manner, the timing of left ventricular pace pulses is set toproduce substantial bi-ventricular mechanical synchronization for thegreatest cardiac output. The determined value of LAVD and thecorresponding LV-RV difference is stored.

[0030] Still referring to FIG. 4, at 106 the pacemaker proceeds to pacethe LV with this established value of LAVD, providing mechanicalsynchronization. Of course, if the natural sinus rate varies, thepacemaker wants to follow; if the spontaneous RAVD varies, but the LAVDdoesn't follow the change, the mechanical synchronization will be lost.Accordingly, at 107 the pacer monitors the natural sinus rate, or atrialpacing rate, and determines if there has been a significant change inatrial rate. If yes, at 109, the pacer adjusts LAVD accordingly tomaintain mechanical sync for optimum output. Although not shown, thepacemaker can periodically go back to block 101 to re-determine thedesired value of LAVD.

[0031] Referring now to FIG. 5, there is shown a flow diagram for pacingof a patient with IAB; such patient may have LBBB as well. Here, it isnecessary to take control of the LA by pacing before atrialdepolarization is conducted (late) to the LA. At 110, the pacemakermonitors the pattern of LA depolarization relative to RA depolarization,i.e., it determines the inter-atrial delay. At 111, it is determinedwhether the LA should be paced, based on the atrial depolarizationpattern. If yes, the pacemaker sets an RA-LA delay at 112, whichcorresponds to a healthy heart, and which enables capture of the LA. At114, the value of RMAVD is obtained, as was described 1 5 in connectionwith FIG. 4. Then, at 116, LAVD is determined for a first setting ofmechanical sync; this can be done by setting LAVD to produce LVcontraction at the same time as RV contraction (valve closure), orearlier by a small time increment. Then, LAVD is varied, as shown at117, and LMAVD and CO are determined corresponding to each value ofLAVD. The value of LAVD is set to that value which corresponds tomaximum cardiac output, and this value and the LV-RV mechanicalrelation, or mechanical sync value is stored for the chosen LAVD. At118, the pacemaker paces LA and LV, in accord with the values that havebeen determined. In the event of significant change in atrial rate, LAVDis adjusted to compensate for the rate change, and to substantiallymaintain the LV-RV mechanical relationship previously found tocorrespond to maximum cardiac output, as shown at 120, 121. Although notshown, in the event of large changes in the sinus rate, or passage of apredetermined amount of time, determination of inter-atrial delay andLAVD can be repeated automatically.

[0032] Referring now to FIG. 6, there is shown a simplified flow diagramfor a procedure in accordance with this invention for carrying outbi-ventricular pacing so as to maximize cardiac output (CO). Thisroutine is adapted for patients who need right ventricular pacing, andwho can benefit from synchronous left ventricular pacing as well. Inthis example, it is assumed that atrial pacing is not required, but ifthe patient requires atrial pacing, the routine can be adaptedappropriately.

[0033] At block 130, a common value of AV delay (AVD) is first set. Atblock 132, both the left ventricle and the right ventricle are paced,initially with the previously set value of AVD, but then with a varyingAVD. As AVD is varied, or scanned relative to the initial setting, thepacemaker makes determinations of cardiac output by processing impedancesignals from the left heart, or left ventricle, in the manner discussedabove. Values of CO are stored together with the different values ofAVD, and the optimum value of a common AVD is determined correspondingto maximum CO. Then, at block 134, the value of LAVD is varied relativeto RAVD, such that the left pacing pulse is delivered at differing timesfrom the right pacing pulse. It is to be remembered, as discussed above,that for maximum cardiac output, it may be desirable to pace the leftventricle shortly before the right ventricle, and this step is asearching step to determine the time relationship between the twoventricular pace pulses which results in the best cardiac output. CO isdetermined as the ventricular sync relationship is varied, and thecorresponding optimum LAVD is determined. When this has been obtained,the routine goes to block 136 and paces the patient at the determinedvalues of LAVD and RAVD. Periodically, as indicated at 138, thepacemaker can determine whether a test is desired. If yes, the routinebranches back to 130, to loop through the test and redetermine theoptimum values of LAVD and RAVD. It is to be noted that the steps ofblocks 132 and 134 can be done in a reverse sequence, i.e., step 134first and then step 132.

[0034] Referring now to FIG. 7, there is shown an alternate blockdiagram of component portions of a pacemaker in accordance with thisinvention, for providing maximum flexibility in terms of pacing, cardiacsignal sensing and impedance sensing. At least two electrodes arepositioned in or proximate to each heart chamber, in the manner asdiscussed above in connection with FIG. 1, and connected in turn toblock 150. As indicated in FIG. 7, block 150 is an output/input switchmatrix, and interconnects with block 152 in the manner as described inFIG. 3. Thus, block 152 provides pacing pulses which can be connectedthrough matrix 150 to each of the four chambers, and has sense amplifiercircuitry for sensing signals from each of the four chambers. Block 150further provides a multiplex switch array for switching a current sourceacross selected pairs of the eight electrodes for impedance measuringpurposes, again in accordance with the discussion of FIG. 3. The sensedimpedance signals are suitably transferred from array 150 to digitalsignal processing circuitry 161, which is part of block 152. Block 152is in two-way connection with the timing modules shown in block 154, fortiming generation of pace pulses, current source pulses, and thegeneration of sensing windows. Blocks 150, 152 and 154 are furtherinter-connected by control bus 163. Data is transferred between signalprocessing block 170 and block 154 across data bus 157. Block 154 inturn is inter-connected with microprocessor 156, through household bus151, data bus 153 and control bus 154. By this arrangement, impedancesensing can be carried out across any combination of the four heartchambers, e.g., right atrium vs. left atrium; right ventricle vs. leftventricle; right atrium vs. left ventricle; and left atrium vs. rightventricle. Impedance measurements between these combinations of chamberscan be carried out in accordance with this invention, for purposes ofanalyzing and confirming arrhythmias, including fibrillation. Further,changes in conduction patterns, as seen in the morphology of suchimpedance measurements, can be monitored and processed for makingdeterminations of progression of heart failure. Thus, cross-measurementsof RA-LV and LA-RV can be useful in obtaining histories to determinechanges indicating progression of heart failure.

[0035] Referring now to FIG. 8A, at block 160, the pacemaker firstobtains impedance measurements either between LA and RA, or between LVand RV. These impedance values are processed at 162, and at 164 adetermination is made as to whether the atrial or ventricular rhythmsare regular or non-physiological. This determination can be made, forexample, simply by sensing differences over time and comparing suchdifferences to predetermined criteria. If a rhythm is determined not tobe regular, then a determination of arrhythmia is made at 166. Asuitable response is made at 168. Referring to FIG. 8B, at block 170 thepacemaker obtains cross-measurements of impedances, e.g., between RA andLV or between LA and RV. These measurements are stored and processed asindicated at 172, and evaluated at 174 to determined whether theyindicate HF or progression toward HF. If yes, an appropriate responsecan be made, illustrated at 176, e.g., providing a warning which can beretrieved by an external programmer.

[0036] The scope of the invention extends to other conditions of CHF, inaddition to the ones illustrated here. In each case, the condition ofthe patient must be responded to on an individual basis. However, inaccordance with this invention, the system response includes adetermination of mechanical events, e.g., valve closure, preferably ineach side of the heart, and programming of pacing escape intervals basedon consideration of the mechanical events and a determination ofvariations of cardiac output with variations of LAVD and/or mechanicalventricular synchronization. The system of this invention can be used inan implanted pacemaker system; or, the system procedures can be carriedout with an external system, for determination of optimum programming ofa pacemaker which is to be implanted or re-programmed.

1. A pacing system for providing pacing of a patient's left heart,comprising: first means for obtaining indications of mechanicalcontractions of the right ventricle; left ventricular pacing means forpacing the left ventricle; and LV control means for controlling thetiming of said left ventricular pacing relative to indicated rightventricular mechanical contractions:
 2. The pacing system as describedin claim 1, comprising second means for obtaining indications ofmechanical contractions of the left ventricle, and wherein said LVcontrol means has means for controlling the timing of said leftventricular pacing so as to provide substantially synchronous left andright ventricular mechanical contractions.
 3. The pacing system asdescribed in claim 1, wherein said LV control means has means fordelivering a left ventricular pacing pulse just before the expected timeof the next right ventricular mechanical contraction.
 4. The pacingsystem as described in claim 2, comprising left atrial pacing means forpacing the patient's left atrium; left AV control means for controllingthe left AV delay between pacing the left atrium and the left ventricle,cardiac output means for measuring left heart output as a function ofsaid left AV delay, and wherein said left AV control means furthercomprises maximizing means for adjusting said left AV delay to maximizeleft cardiac output.
 5. The pacing system as described in claim 4,comprising means for sensing sinus signals, and left atrial timing meansfor timing delivery of left atrial pacing pulses relative to said sinussignals.
 6. The system as described in claim 1, wherein said first meanscomprises an impedance measuring circuit for obtaining an impedancesignal representative of impedance between the patient's right atriumand right ventricle, and processing means for processing said impedancesignal to determine the timing of right heart valve closures.
 7. Thesystem as described in claim 1, comprising second impedance means forobtaining a left impedance signal representative of impedance changeover the patient's left heart, and second processing means forprocessing said left impedance signal to obtain a measure of left heartoutput.
 8. The system as described in claim 7, comprising thirdprocessing means for processing said left impedance signal to obtainfilling signals indicative of the filling of the left ventricle, andwherein said LV control means comprises means for controlling timing ofsaid left ventricular pacing signals as a function of said fillingsignals.
 9. The system as described in claim 1, further comprising meansfor obtaining indications of left ventricular mechanical contractions,and wherein said LV control means comprises mechanical sync means forcontrolling said left ventricular pacing to achieve mechanical synchronyof said left and right mechanical contractions.
 10. The system asdescribed in claim 9, wherein said mechanical sync means comprisesadjusting means for adjusting the timing of aid left ventricular pacingso as to maximize left heart output.
 11. A four-chamber pacing systemfor providing pacing of a patient's left heart to improve cardiacoutput, comprising: RV means for determining the timing of rightventricular mechanical contractions; LV means for determining the timingof left ventricular mechanical contractions; and pacing sync means forpacing the patient's left ventricle; and control means for controllingsaid pacing means so as to substantially synchronize said left and rightmechanical contractions;
 12. The four-chamber pacing system as describedin claim 13, comprising: LA means for determining the timing of leftatrial depolarization; CO means for measuring cardiac output from thepatient's left heart; and wherein said control sync means comprises LAVDmeans for controlling said pacing means to deliver pacing pulses to saidpatient's left ventricle at a left atrio-ventricular delay followingleft atrial depolarizations, and adjusting means for adjusting said leftatrio-ventricular delay to correspond to maximum measured cardiacoutput.
 13. A system for bi-ventricular pacing, comprising: RVPgenerating means for generating and delivering pacing pulses to thepatient's right ventricle; LVP generating means for generating anddelivering pacing pulses to the patient's left ventricle; atrial sensemeans for determining the cyclical time of excitation of the patient'sright and left atria; RAVD control means for controlling said RVPgenerating means to deliver pace pulses at a predetermined RAVD delayfollowing right atrial activation; LAVD control means for controllingsaid LVP generating means to generate pace pulses at an LAVD delayfollowing left atrial activation; output means for determining a measureof cardiac output from the patient's left ventricle; adjusting means foradjusting said LAVD and RAVD delays and determining the optimumrelationship of said LAVD and RAVD delays which results in maximizedcardiac output; and program means for programming said RAVD controlmeans and said LAVD control means to control delivery of pacing pulsesto the left and right ventricles with said optimum relation.
 14. Thesystem as described in claim 13, comprising second adjusting means foradjusting said LAVD and RAVD equally, and wherein said output meansobtains values of LAVD and RAVD corresponding to maximum cardiac outputand wherein said program means controls said RAVD control means and saidLAVD control means to deliver pacing pulses with said values.
 15. Thesystem as described in claim 14, comprising means for obtaining thedifference between LMAVD and RMAVD corresponding to optimized cardiacoutput, and means for maintaining said difference.
 16. A method ofcardiac pacing, comprising: cyclically determining mechanical eventsindicative of left ventricular contraction and right ventricularcontraction; cyclically determining cardiac output from the patient'sleft ventricle; pacing said patient's left ventricle with varying timingrelative to said right ventricular contractions and determining therelative mechanical synchronization of left ventricular and rightventricular contractions which results in maximum cardiac output; andmaintaining said relative mechanical synchronization.
 17. A method asdescribed in claim 16, comprising: determining atrial excitations of thepatient; controlling delivery of each left ventricular pace pulse at anLAVD delay following each said atrial excitation; and adjusting saidLAVD to obtain said relative mechanical synchronization for optimumcardiac output.
 18. The method as described in claim 16, comprisingpacing the patient's right ventricle at an RAVD delay a following saidatrial excitation, and controlling said RAVD and LAVD delays to maintainsaid relative mechanical synchronization.
 19. The method as described inclaim 17, comprising:
 20. A method of bi-ventricular pacing, comprisingsensing sinus signals from the patient's right atrium; cyclicallygenerating and delivering left and right ventricular pace pulses forpacing the patient's left and right ventricles respectively; cyclicallydetermining a measure of cardiac output from the patient's leftventricle; and adjusting the relative timing of said left and rightventricular pace pulses to correspond to maximum cardiac output.
 21. Themethod as described in claim 20, comprising sensing patient-sinussignals, timing out an LAVD delay between a sensed sinus signal anddelivery of the left ventricular pace pulse and an RAVD delay between asensed sinus signal and delivery of a right ventricular pace pulse,varying said LAVD delay relative to said RAVD delay, and determining therelationship between said LAVD delay and said RAVD delay which resultsin said maximum cardiac output.
 22. The method as described in claim 21,having electrodes positoined in each of a patient's four heart chambers,comprising further adjusting both said LAVD and RAVD delays by equalamounts and determining the values of said delays corresponding tomaximum cardiac output.
 23. A four chamber pacing system, havingelectrodes positioned in each of a patient's four heart chambers,comprising: impedance means for obtaining impedance measurements betweena selected pair of said four chambers; processing means for processingsaid impedance measurements, and determining changes in saidmeasurements over a period of time; and determining means fordetermining whether any said change occurs which indicates a physicallyabnormal heart condition.
 24. The system as described in claim 22,wherein said determining means determines whether any such change occurswhich is indicative of an arrhythmia.
 25. The system as described inclaim 22, wherein said determining means comprises means for determiningwhether said any such change occurs which indicates a heart failurecondition.
 26. The system as described in claim 22, comprisingprogrammable selection means for selecting impedance measurementsbetween any two of said four heart chambers.